Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features.

Impairment of ubiquitin-proteasome system activity involving ubiquitin ligase genes UBE3A, UBE3B, and HUWE1 and deubiquitinating enzyme genes USP7 and USP9X has been reported in patients with neurodevelopmental delays. To date, only a handful of single-nucleotide variants (SNVs) and copy-number variants (CNVs) involving TRIP12, encoding a member of the HECT domain E3 ubiquitin ligases family on chromosome 2q36.3 have been reported. Using chromosomal microarray analysis and whole-exome sequencing (WES), we have identified, respectively, five deletion CNVs and four inactivating SNVs (two frameshifts, one missense, and one splicing) in TRIP12. Seven of these variants were found to be de novo; parental studies could not be completed in two families. Quantitative PCR analyses of the splicing mutation showed a dramatically decreased level of TRIP12 mRNA in the proband compared to the family controls, indicating a loss-of-function mechanism. The shared clinical features include intellectual disability with or without autistic spectrum disorders, speech delay, and facial dysmorphism. Our findings demonstrate that E3 ubiquitin ligase TRIP12 plays an important role in nervous system development and function. The nine presented pathogenic variants further document that TRIP12 haploinsufficiency causes a childhood-onset neurodevelopmental disorder. Finally, our data enable expansion of the phenotypic spectrum of ubiquitin-proteasome dependent disorders.

A proposed pediatric risk stratification method (PRiSM) for disaster preparedness.

OBJECTIVE: Children are a uniquely vulnerable population in times of disaster. Understanding the risk associated with the pediatric population is complex and involves aspects beyond just the medical needs of children. DESIGN: We reviewed current literature in two databases regarding risk and disaster preparedness in children to assess current risk stratification methodologies across multiple domains including medical, social, and educational. RESULTS: No comprehensive risk stratification tool exists that considers multiple domains. Three key domains are inter-related to a child's vulnerability in times of disaster; medical, educational, and social. We propose a pediatric risk stratification method (PRiSM) for disaster preparedness as one way to consider the three critical domains. Using existing medical, educational, and social data, our proposed framework considers all three domains to stratify children by their degree of risk in terms of disaster preparedness. PRiSM consists of a three-digit alphanumeric guide to stratify patients based on complex medical, educational, and social needs. CONCLUSION: This framework provides a possible method to risk stratify children prior to a disaster to better inform planning and responses in the future.